human male infertility, the y chromosome, and dinosaur ......extinction while the dinosaurs and at...

Middle East Fertility Society Journal (2011) xxx, xxx–xxx

Middle East Fertility Society

Middle East Fertility Society Journal

www.mefsjournal.comwww.sciencedirect.com

OPINION ARTICLE

Human male infertility, the Y chromosome, and dinosaur

extinction

Sherman J. Silber *

Infertility Center of St. Louis, St. Luke’s Hospital, St. Louis, MO, USAAcademic Medical Center (AMC), Amsterdam, The Netherlands

Received 18 November 2010; accepted 18 January 2011

KEYWORDS

Dinosaur extinction;

Sex chromosomes;

Y chromosome;

Climate change;

Male infertility

* Address: Infertility Center o

South Woods Mill Road, Suite

+1 314 576 1400; fax: +1 314

E-mail address: silber@infertile

1110-5690 � 2011 Middle E

hosting by Elsevier B.V. All rig

Peer review under responsibilit

doi:10.1016/j.mefs.2011.01.001

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Abstract Study of the molecular genetics of human male infertility and the Y chromosome has

helped to elucidate the evolution of our X and Y chromosomes. Particularly, the study of the Y

chromosome in male infertility has also helped to clarify, in a surprising and unexpected way, a

likely mechanism for dinosaur extinction, the biggest question all of us have entertained from

our earliest childhood days.

There have been many claims in the popular press of ‘‘discoveries’’ on how the dinosaurs went

extinct. These claims all relate to climate change events that occurred 65 million years ago that

no one disputes occurred. But none have explored the biology of how so many animals escaped

extinction while the dinosaurs and at least half of all other species did not. For example, why

did large dinosaurs, as well as small dinosaurs the same size as chickens go extinct, but birds sur-

vived? Possibly the evolution of sex chromosomes holds the answer to this question.

Our studies of the Y chromosome and male infertility suggest that the default mechanism for

determining the sex of offspring is the temperature of egg incubation, and that genetic sex determi-

nation (based on sex chromosomes like X and Y) has evolved many times over and over again in

different ways, in different genera, as a more foolproof method than temperature variation of assur-

ing a balanced sex ratio in offspring. The absence of such a genetic sex determining mechanism in

uis, St. Luke’s Hospital, 224

Louis, MO 63017, USA. Tel.:

.

lity Society. Production and

ved.

dle East Fertility Society.

lsevier

Silber SJ Human male infertility, the Y chromosome, and dinosaur extinction, Middle Eastefs.2011.01.001

mailto:[email protected]

http://dx.doi.org/10.1016/j.mefs.2011.01.001



http://www.sciencedirect.com/science/journal/11105690


Figure 1 The Y chromosome evolve

was originally just an ancestral pair

with degeneration of its X homologo

‘‘male benefit’’ genes.

2 S.J. Silber

Please cite this article in press as:Fertil Soc J (2011), doi:10.1016/j.m

dinosaurs may have led to a skewed sex ratio when global temperature dramatically changed

65,000,000 years ago, resulting in a preponderance of males, and consequentially a rapid decline

in population.

� 2011 Middle East Fertility Society. Production and hosting by Elsevier B.V. All rights reserved.

1. Introduction

Genetically based sex determination mechanisms have evolvedindependently in many different genera numerous times overthroughout the history of life on earth to ensure a balanced

male–female sex ratio (1–13). Mammals, birds, all snakesand most lizards, amphibians, flying insects, worms, and somefish, employ specific ‘‘sex-determining’’ chromosomes or genes

to determine the sex of the embryo. This mechanism is gener-ically termed GSD, for ‘‘genetic sex determination.’’ In mam-mals, GSD is controlled by the SRY gene on the smaller Y

chromosome of the male. Contrastingly, in birds and snakes,who also use GSD, the smaller sex chromosome results infemale rather than male offspring.

Not all animals employ GSD for sex determination.

Crocodiles and alligators, turtles, some lizards, and many fishemploy environmental, or temperature-dependent sex determi-nation (TSD) of offspring. This means that there is no genetic

predetermination of gender. In these animals, it is merely thetemperature at which the early embryos are incubated thatdetermines whether the primitive gonad will differentiate into

a testis or an ovary.Temperature dependent sex determination (TSD) is

thought to be the primordial mechanism that triggers either

testicular or ovarian development in the early embryo (7–9).The embryonic development of the testis or the ovary from aprimitive gonad is the product of a multitude of well-conservedgenes. The sex-determining gene (like SRY in the mammals) is

simply a trigger to activate that downstream cascade of manyother genes elsewhere in the genome that actually orchestratetestis or ovarian development (Fig. 1). The various modes of

d over 300 years from what

of ordinary chromosomes,

us genes and recruitment of

Silber SJ Human male infertiliefs.2011.01.001

genetic sex determination (GSD) have evolved many times to

override TSD, completely independently and differently, inthe history of life on earth (3,4,12,13). There is no similarityof the Y chromosome or the sex-determining ‘‘trigger’’ gene

in mammals, lizards, drosophila, or worms, except that themale determining chromosome (by definition the Y) is smallerthan its counterpart (the X). In snakes and birds, the femaledetermining trigger gene (the W by definition) is smaller than

its counterpart (the Z), but they are completely different fromeach other in all genera.

Evolution, therefore, appears to favor the eventual repeated

appearance of genetic based sex determination (GSD), we pos-tulate, because animals not using this mechanism are at risk ofextinction due to a skewed sex ratio that could result from

massive global environmental temperature change. If thereare multiple generations of a preponderance of male offspring,the species cannot survive. This recurring hazard favors the re-

peated evolution of a sex determining ‘‘trigger’’ gene in all gen-era (to protect against the disastrous effect of environmentalvicissitudes on the sex ratio of offspring).

Global temperature spikes predictably occur every

100,000 years, and to a lesser extent in harmonics of every25,000 years (1) (Fig. 2). A massive global temperature changecan skew the sex ratio of TSD offspring and we have postu-

lated that this played a role in the demise of the dinosaurs.Global warming today, which far exceeds the usual 100,000-year spike, similarly represents a current risk for extant TSD

species. This theory originally suggested in 1989, was basedon paleontologic evidence, before we understood the unusualsequence of the Y chromosome and the evolution of sex chro-

mosomes (2). But now our better understanding of the DNAsequence of sex chromosomes, and of the survival of aviandinosaurs, gives even stronger credence to such a view.

Figure 2 Global temperature independent of man spikes every

100,000 years which encourages the evolution of sex chromosomes

to assure a balanced sex ratio.

ty, the Y chromosome, and dinosaur extinction, Middle East


Figure 4 A complete predator dinosaur found intact in Gobi

Desert in Mongolia.

Human male infertility, the Y chromosome, and dinosaur extinction 3

Despite the survival advantage of genetic sex determina-tion, there is, however, a survival disadvantage. The disadvan-tage of an evolving sex determining chromosome (which

guarantees a balanced sex ratio) is its eventual decay causedby the absence of meiotic recombination during gametogene-sis, and in humans the subsequent loss of spermatogenesis

genes, causing male infertility. This mechanism has been con-firmed in studies of infertile males, in association with the fullsequencing of the Y chromosome (3,4). Hence, despite the pro-

tection that GSD affords against catastrophic global tempera-ture shifts, and its necessity for the evolution of endothermicmammals, male infertility is increased because of the accumu-lation on the Y chromosome of a dense concentration of sper-

matogenesis genes in a region that is chromosomally unstablebecause of failure of chromosomal recombination during mei-osis (Fig. 3). Similarly a ZZ–ZW system may have protected

birds from the global K-T extinction of their cousins, the dino-saurs and flying pterosaurs. However, female birds only haveone working ovary, and if it is removed, the remaining vestigial

gonad becomes a testis. So we might speculate that the ZZ–ZW female bird may have avoided global extinction byemploying a GSD based mechanism for sex determination,

but may have paid a price for this by having only one ovary.The human male’s price for this GSD security is the risk ofdeclining sperm count caused by Y chromosomal deletions.

Thus, unexpectedly, through our efforts to understand the

molecular genetics of male infertility, we may have stumbledupon one explanation for the deepest mystery of our child-hood, and our biggest fear, extinction (Fig. 4).

2. Sex determination and extinction

Genetic modes of sex determination (GSD) in unrelated ani-

mals have arisen independently many times over (14–16). De-

Figure 3 The Y chromosome cannot repair itself by ordinary

meiosis with its homologous mate, and therefore, has to try to

recombine with itself (gene conversion).

Please cite this article in press as: Silber SJ Human male infertiliFertil Soc J (2011), doi:10.1016/j.mefs.2011.01.001

spite highly varied ‘‘triggering’’ mechanisms in a variety ofvertebrates, most animals share the same or similar, highlyconserved downstream genes that control sex differentiation.The genes that cause the primitive embryonic gonad to become

a testis or an ovary are virtually the same for all animals on theplanet. Thus, the downstream genetic programs involved inboth GSD and environmental modes of sex determination

(TSD) are closely related. This is perhaps not unexpected, gi-ven that the development of the testis and ovary and their con-stituent cells is broadly similar in amphibians, reptiles,

mammals, and birds. However, the mechanisms, whetherGSD or TSD, which trigger those downstream genes to directtestis or ovary development from the primordial indifferent go-nads are quite different. TSD animals rely on a potentially pre-

carious relationship with their environment where a balancedsex ratio is dependent on the temperature of egg incubation(Fig. 5) (5,17–19). Whether a sex-determining gene or random

variation in temperature of egg incubation, both trigger mech-

Figure 5 Dinosaurs laid their eggs in nests similar to crocodil-

ians where temperature variation was the rule.



Figure 6 Evolution of animals on Earth before and after

extinction of dinosaurs – a review of this summary of the

evolution of life on earth demonstrates several major extinction

events related to massive global environmental changes. The K-T

event of 65 million years ago resulted in sudden loss of the most

dominant animals in history, the dinosaurs.

4 S.J. Silber

anisms have the same common goal of assuring a balancedmale–female sex ratio.

While the precise environmental effects of the great impactevent of 65 million years ago are open to debate, it is not con-tested that profound global environmental changes occurred

that led to the extinction of dinosaurs (20). Yet this global‘‘K-T’’ event 65 million years ago, when the dinosaurs went ex-tinct, did not cause the mass extinction of mammals, birds,fruitflies, frogs, or snakes (Fig. 6). We suggest the reason for

this could be that changes in global temperature would havehad a more pronounced extinction effect on TSD-dependentanimals than on animals using GSD (2). However, we must an-

swer why alligators, crocodiles, and turtles (which are alsoTSD animals) survived the K-T event even though dinosaursand pterodactyls did not, and how this theory might be tested.

Every few months another paper makes media news claim-ing that the cause for the extinction of the dinosaurs has beendiscovered. But it is always about the giant asteroid or the vol-canic activity 65 million years ago, and never about the actual

physiology of the animals themselves, that might have madesome prone to extinction (like the dinosaurs) and others not.It is possible that without the recurrent evolution of GSD sys-


tems for sex determination, many animals, obviously not all,would go extinct because of a skewed sex ratio in their offspring.

These conclusions are based on a two-way comparison of

dinosaur fossils with extant species, and construction of amathematical population prediction model based on sex ratioskewing (21). We also evaluated the evolution of sex chromo-

somes by studying the mapping and sequencing of the humanX and Y in fertile and infertile men (3,4,14,22–25). We postu-late that the absence of genetic sex determination is very likely

what could have caused the selective extinction of the dino-saurs 65 million years ago.

3. Relationship between dinosaurs and their relatives

Dinosaurs and crocodiles are members of the Archosauria, amajor group of diaspsids that appeared in the Early Triassic,

some 245 million years ago. By the Late Triassic (208 mil-lion years ago) the dominant representatives were dinosaurs,champosaurs, pterosaurs, and crocodilians (26). Modern birdswere derived from avian archosaurs that first appeared during

the Jurassic (about 170 million years ago) and expanded theirrange in the Cretaceous period where they would have sharedthe skies with the dominant pterosaurs (pterodactyls). Crocod-

ilians (TSD-dependent) and birds (GSD-dependent) are theonly Archosaurian taxa that have persisted to this day(27,28). We propose that avians (birds), which are considered

surviving dinosaurs, survived because of their GSD systemfor gender determination. Crocodilians and other TSD species(but not dinosaurs) survived because they could adapt success-fully to the changing environment, or possibly their TSD sys-

tem resulted in a female dominated skewing rather than males.Studies on oviparity in the American alligator demonstrate

a close physiological link between crocodilian and ancient

archosaurian reproductive function (29,30). These compari-sons are significant because they suggest physiological similar-ities between crocodilians and extinct dinosaurs. Birds

developed GSD in parallel with their endothermy some170 million years ago, whereas dinosaurs more likely employedTSD for sex determination. As GSD modes of sex determina-

tion are immune to the environmental vicissitudes that chal-lenge animals using TSD, a strong selection bias favors theadoption of GSD in environments where a deleterious changein temperature becomes a species-threatening issue.

4. Molecular evolution of sex determining chromosomes

The specific chromosomes and genes responsible for GSD have

evolved independently many times over and over again, in in-sects, worms, amphibians, reptiles, birds, and mammals indi-cating significant evolutionary advantages in its development.

Mammals employ a XX–XY, male heterogametic system thatevolved from what were originally autosomes, centered aroundthe emergence of the SRY (testis-determining) gene on the

ancestral Y chromosome between 200 and 300 million yearsago (31–35). Much earlier than this, insect species developeda completely different XX–XY male heterogametic system that

has no relation to the mammalian. Birds employed a femaleheterogametic (ZZ–ZW) system about 150 million years later.This simply means that unlike a XY system where the shortsex chromosome (the Y) determines that the primitive gonad



Figure 8 All nine testis specific spermatogenesis gene families in

the Y exist in the ampliconic multiple (60 members) copy

sequences.


will become a testicle, the short sex chromosome (the W) of thebird determines that the primitive gonad will become an ovary.(It is a little more complicated in ZZ–ZW systems in that the

double dosage of the ZZ in birds could possibly be just as sig-nificant as the single short W.)

The inherent stability of GSD in mammals and birds iron-

ically is due to the subsequent atrophy of the sex-determiningchromosome, e.g. the human Y. The driving force for thisatrophy process is selective failure of meiotic recombination

between the sex chromosomes, leading over time, to the grad-ual degradation of the non-recombining portion of the sex-determining chromosome (Fig. 1). This decay of what was pre-viously an ordinary paired autosome has resulted in selective

hyper-expression and inactivation of its paired mate (X-inacti-vation), bringing parity of gene dosage expression betweenmales and females (16).

ZZ–ZW birds and some advanced snakes have highly het-eromorphic sex chromosomes with extensively atrophied Wchromosomes like the atrophied Y in mammals and in fruit

flies. However, many snakes, and all amphibians, have homo-morphic sex chromosomes, which means that they are virtuallyindistinguishable in size from each other. In many of these spe-

cies with GSD sex chromosomes that are homomorphic, anenvironmentally induced interchangeability of sex determiningmechanisms is occasionally observed. That is, temperature canstill override the genetic sex determination system. No GSD

species with heteromorphic sex chromosomes, however, isknown to display this phenomenon, and evolutionary driveis consistent with GSD eventually dominating TSD due to

its irreversibility once the sex-determining chromosome hasatrophied. Once atrophy of the sex-determining chromosomehas commenced with compensatory hyper-expression of its

mate to provide gene dosage parity, there is no going backto TSD (17,36).

Figure 7 The DAZ gene on the Y is an example of a ‘‘male

benefit’’ gene which transposed from its ancestral position on

human chromosome 3, 30 million years ago, to the Y where it was

amplified fourfold with multiple copies.


5. Evolutionary accumulation of testis specific genes to theY and

the subsequent threat to male fertility

Along with the decay of most of the ancestral autosomal geneson the heterogametic sex chromosome controlling GSD (the Ychromosome in mammals), there is a parallel accumulation ofgenes on the Y that control spermatogenesis (14,15). This inev-

itably occurs because the region next to the testis-determininggene, which does not recombine during meiosis, is a ‘‘safe har-bor’’ for genes that are beneficial to the male but detrimental

to the female (Fig. 7). ‘‘Sexually antagonistic’’ male benefitgenes, which are testis-specific and, therefore, enhance malefertility, but would be detrimental to female fertility, have thus

been accumulated and amplified with generation of multiplecopies and repeat sequences on the non-recombining regionof the Y over the course of 300 million years (Fig. 8). Thus,

a functionally coherent concentration of testis-specific genesin multiple copies has arisen on a labile Y chromosome thatis subject to deletions and inversions caused by massive directand inverted regions of nucleotide identity (amplicons and pal-

indromes), and is a significant cause of human male infertility(3,4,23–25). There is a fragile balance between ‘‘gene conver-sion’’ with chromosome repair by recombination between the

palindrome arms, and their frequent deletion due to a mis-taken homologous recombination between massive ampliconicrepeat sequences on the Y (22). Thus, the inevitable evolution

over and over again of sex-determining chromosomes must bevery important for species survival, since it also can result in amajor threat to male fertility in animals with a Y chromosome.TSD might, however, offer an advantage to some species if the

environmental temperature change were to lead to more fe-males than males. This could have been what saved someTSD species like the turtle and the crocodilians (37).

6. Aromatase and sex determination

For both GSD and TSD, the activity of aromatase is pivotal in

the conversion of testosterone to estradiol. Aromatase isknown to be a key regulatory enzyme directing ovarian devel-



6 S.J. Silber

opment of all TSD animals studied to date(38). Hence, at per-missive (for female development) temperatures, aromatase lev-els rise during early embryogenesis accompanied by rises in

estradiol and ovarian development. At non-permissive temper-atures, aromatase levels remain low while testosterone rises,accompanied by testis development. It is a simple matter to

provide exogenous estrogens to developing eggs incubatingat male determining temperatures and force them to hatch asfemales (9,10,39,40). Similar experiments on chickens show

that male to female sex reversal is observed following intra-ova injection of estradiol, but birds normally revert to a malephenotype as they mature. Mammalian development is lesssensitive to exogenous steroidgenic factors. However, gender

switching can be observed in all TSD reptiles exposed to estro-gens. These experiments demonstrate that the control over aro-matase activity is the key to TSD although how temperature

exerts its control over this enzyme is still unknown.It is, therefore, likely that TSD is the ancient default mech-

anism for sex determination, and it simply relates to differen-

tial enzyme activity at differing incubation temperatures. Themore specialized GSD (or genetic sex-determining) genes likeX and Y or Z and W evolved over and over again in different

genera, superimposed over the default mechanism of TSD (37).

7. Mathematical modeling of skewed sex ratio and testing of

theory

A major question is whether the proposed skewing of sex ratiowas toward male or toward female, and how severe a skewingwould be required for extinction to occur, as well as how many

generations of skewed sex ratio would be required to result inextinction? To answer these questions we developed a detailedmathematical model (21,41). A skewing of 90% male would re-

sult in an initial population decline, but then a robust recoveryif the sex ratio balance were restored within 50 generations.However, populations would inexorably decline to extinction

if the skew would take longer than 50 generations to correct.Thus, a prolonged but modest skewing toward male predomi-nance in the gender of dinosaur offspring over 50 generations

(probably only 1000 years, which is very brief in paleontologictime) would have led to extinction. A more severe male pre-dominance could lead to a rapid extinction in just a few gener-ations. Even a more modest skew of 80:20 would result in

extinction if the skewing were to continue.However, a skewing of 60:40 males to females would not

lead to extinction even over a prolonged period. A predomi-

nance of female births even over an extended period is not suf-ficient for population collapse if some males are available.Therefore, it is very unlikely that a skewing toward predomi-

nantly females would result in extinction. Indeed, this maybe one reason why crocodilians and turtles survived the K-Tevent even though dinosaurs went extinct. A preponderanceof females would not be as deleterious as a preponderance of

males, and might have even been advantageous to crocodiliansand turtles (42,43).

8. Conclusions

TSD was the forerunner to GSD. Most or all of the genes con-trolling testis or ovary formation in TSD had already evolved

prior to the appearance of GSD in early mammal-like reptiles.


Probably all forms of GSD use molecular switches that wereoriginally derived from one of these primordial testis or ovarygenes. For example, a single gene related to SOX3 on the

ancestral X autosome became the primary switch (SRY) forsex determination in mammals, and was all that was neededfor GSD to first evolve in mammal-like reptile species some

250–300 million years ago. As this group is credited with beingthe forerunner of the mammals, these sex chromosomes wouldhave been the forerunners of the modern mammalian XY pair

that use SRY as the sex-determining switch. The ZW chromo-somes independently developed a sex-determining role insnakes and birds about 100 million years later protecting themfrom the population skewing which dinosaurs suffered.

The phylogenetic relationship between crocodiles and dino-saurs supports the hypothesis that the archosaurian lineageemployed TSD as their default sex determining mechanism.

The relatively clement environments enjoyed by animals inthe Jurassic and early Cretaceous would not have driven theirswitching to GSD. Thus the post K-T climatic change would

have resulted in skewing of the sex ratio toward a preponder-ance of males for a period that was too prolonged to permitpopulation recovery. This theory has modern day implications.

The current global warming trend is so extreme that it is al-ready affecting leatherback sea turtle survival off the coast ofCosta Rica for this very same reason of the birth of a skewedsex ratio in their offspring because of a rise in the beach tem-

perature (44). Thus, we humans may be creating conditions foranother massive global extinction of TSD animals, similar towhat occurred 65,000,000 years ago.

References

(1) Talbot D. CO2 and the ‘‘Ornery Climate Beast’’. Technol Rev

2006:41.

(2) Paladino FV et al. Temperature-dependent sex determination in

dinosaurs? Implications for population dynamics and extinction.

Geol Soc Am SP 1989;238:63–70.

(3) Kuroda-Kawaguchi T et al. The AZFc region of the Y chromo-

some features massive palindromes and uniform recurrent dele-

tions in infertile men. Nat Genet 2001;29:279–86.

(4) Skaletsky H et al. The male-specific region of the human Y

chromosome is a mosaic of discrete sequence classes. Nature

2003;423:825–37.

(5) Pieau C, Dorizzi M, Richard-Mercier N. Temperature-dependent

sex determination and gonadal differentiation in reptiles. Cell

Mol Life Sci 1999;55:887–900.

(6) Yntema CL. Effects of incubation temperature on sexual differ-

entiation in the turtle. J. Morphol 1976;150:453–62.

(7) Head G, May RM, Pendleton L. Environmental determination of

sex in the reptiles. Nature 1987;329:198–9.

(8) Bull JJ. Sex determining mechanisms: an evolutionary perspec-

tive. Experientia 1985;41:1285–96.

(9) Wibbels T, Bull JJ, Crews D. Chronology and morphology of

temperature-dependent sex determination. J Exp Zool

1991;260:371–81.

(10) Wibbels T et al. Estrogen and temperature induced medullary

cord regression during gonadal differentiation in a turtle. Differ-

entiation 1993;53:149–54.

(11) Crews D, Bergeron JM. Role of reductase and aromatase in sex

determination in the red-eared slider, a turtle with temperature-

dependent sex determination. J Endocrinol 1994;143:279–89.

(12) Crews D. Temperature, steroids and sex determination. J Endo-

crinol 1994;142:1–8.




(13) Ferguson MW, Joanen T. Temperature of egg incubation deter-

mines sex in Alligator mississippiensis. Nature 1982;296:850–3.

(14) Saxena R et al. The DAZ gene cluster on the human Y

chromosome arose from an autosomal gene that was transposed,

repeatedly amplified and pruned. Nat Genet 1996;14:292–9.

(15) Lahn BT, Page DC. Functional coherence of the human Y

chromosome. Science 1997;278:675–9.

(16) Jegalian K, Page DC. A proposed path by which genes common

to mammalian X and Y chromosomes evolve to become X

inactivated. Nature 1998;394:776–80.

(17) Janzen FJ, Paukstis GL. Environmental sex determination in

reptiles. Nature 1988;332:790.

(18) Janzen FJ, Paukstis GL. Environmental sex determination in

reptiles: ecology, evolution, and experimental design. Q Rev Biol

1991;66:149–79.

(19) Janzen FJ. Climate change and temperature-dependent sex

determination in reptiles. Proc Natl Acad Sci USA

1994;91:7487–90.

(20) Schulte P et al. The Chicxulub asteroid impact andmass extinction

at the Cretaceous-Paleogene boundary. Science 2010;327:1214–8.

(21) Miller D, Summers J, Silber S. Environmental versus genetic sex

determination: sex chromosomes and dinosaur extinction? Fertil

Steril 2004;81:954–64.

(22) Rozen S et al. Abundant gene conversion between arms of

palindromes in human and ape Y chromosomes. Nature

2003;423:873–6.

(23) Silber SJ et al. Y chromosome deletions in azoospermic and

severely oligozoospermic men undergoing intracytoplasmic sperm

injection after testicular sperm extraction. Hum Reprod

1998;13:3332–7.

(24) Silber SJ, Repping S. Transmission of male infertility to future

generations: lessons from the Y chromosome. Hum Reprod

Update 2002;8:217–29.

(25) Silber S. The disappearing male. In: Jansen R, Mortimer D,

editors. Towards reproductive certainty-fertility and genetics

beyond 1999. New York and London: The Panthenon Publishing

Group; 1999. p. 499–505.

(26) Serono PC. The evolution of dinosaurs. Science

1999;284:2137–47.

(27) Norell M et al. Palaeontology: ‘‘modern’’ feathers on a non-avian

dinosaur. Nature 2002;416:36–7.

(28) Norell MA, Clarke JA. Fossil that fills a critical gap in avian

evolution. Nature 2001;409:181–4.


(29) Palmer BD, Guillette Jr LJ. Alligators provide evidence for the

evolution of an archosaurian mode of oviparity. Biol Reprod

1992;46:39–47.

(30) Rogers SW. Allosaurus, crocodiles, and birds: evolutionary clues

from spiral computed tomography of an endocast. Anat Rec

1999;257:162–73.

(31) Rice WR. Degeneration of a nonrecombining chromosome.

Science 1994;263:230–2.

(32) Ohno S. Sex chromosomes and sex-linked genes. Berlin: Springer-

Verlag; 1967.

(33) Graves JA. The evolution of mammalian sex chromosomes and

the origin of sex determining genes. Philos Trans R Soc Lond B:

Biol Sci 1995;350:305–12.

(34) Delbridge ML, Graves JA. Mammalian Y chromosome evolution

and the male-specific functions of Y chromosome-borne genes.

Rev Reprod 1999;4:101–9.

(35) Marshall Graves JA, Shelty S. Sex from W to Z: evolution of

vertebrate sex chromosomes and sex determining genes. J Exp

Zool 2001;290:449–62.

(36) Doumon C, Houillon C, Pieau C. Temperature sex-reversal in

amphibians and reptiles. Int J Dev Biol 1990;34:81–92.

(37) Scherer G, Schmid M. Genes and mechanisms in vertebrate sex

determination. Berlin: Berkhauser, Verlag; 2001.

(38) D’Cotta H et al. Aromatase plays a key role during normal and

temperature-inducted sex differentiation of tilapia. Mol Reprod

Dev 2001;59:265–76.

(39) Vaillant S et al. Sex reversal and aromatase in chicken. J Exp

Zool 2001;290:729–40.

(40) Wibbels T, Bull JJ, Crews D. Synergism between temperature and

estradiol: a common pathway in turtle sex determination? J Exp

Zool 1991;1260:130–4.

(41) Girondot M, Pieau C. Effects of sexual differences of age at

maturity and survival on population sex ratio. Evol Ecol

1993;7:645–50.

(42) Silber S, Geisler JH, Bolortsetseg M. Unexpected resilience of

species with temperature-dependent sex determination at the

Cretaceous-Palaeogene boundary. Biol Lett 2010. doi:10.1098/

rsbl.2010.0882 [published online].

(43) Clinton M. Sex determination and gonadal development: a bird’s

eye view. J Exp Zool 1998;281:457–65.

(44) Rosenthal E. Turtles are casualties of warming in Costa Rica. The

New York Times 2009:A8 [November 14].


http://dx.doi.org/10.1098/rsbl.2010.0882

http://dx.doi.org/10.1098/rsbl.2010.0882


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